The proposed project will map and clone the gene for frontotemporal dementia (FTD), a clinically and pathologically heterogeneous disorder that has been localized to chromosome 17q21-22. The PI and colleagues have identified a series of FTD families with significant linkage to this region, and they have narrowed the locus to 2-3 cM. They now propose to gather and analyze additional families through research centers in the US and Sweden. The additional families will be used to further delineate the disease locus by segregation analysis (identification of recombinants) and allelic association. The obligate genetic region will be physically mapped and cloned. Candidate genes will be identified from amongst transcripts already known to exist in the region and newly identified clones. The candidates will be prioritized by expression pattern, presence of CAG repeats, and sequence homology. The candidate genes will then be sequenced in FTD patient samples to identify mutations specific to the disease. After the gene is identified, further plans include genotype-phenotype correlation study, sequence analysis, and analysis of the effects of the mutations in vitro and in vivo.